FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles) in

patients with initially resectable metastatic colorectal cancer. A GERCOR Randomized Phase III study (MIROX)

M. Hebbar, B. Chibaudel, T. André, L. Mineur, D. Smith, C. Louvet, J.L. Dutel, M. Ychou, J.L. Legoux, M. Mabro, R. Faroux, D. Auby,

D. Brusquant, A. Khalil, S. Truant, A. Hadengue, F. Bonnetain, FR. Pruvot, C. Dalban, A. de Gramont

CONFLICT OF INTEREST DISCLOSURE

No conflict of interest to declare

Liver is the main metastatic site in patients with colorectal cancerMetastases are initially resectable in 15-20 % patientsPerioperative FOLFOX chemotherapy is active (EORTC study)

RATIONALE

Nordlinger B, et al. Lancet 2008, 371:1007-16

HR= 0.73[CI: 0.55-0.97]

P=0.025

Surgery only

Periop FOLFOX4

33.2%

42.4%

(years)0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

PF

S in

res

ecte

d pa

tient

s (%

)

3-yr PFS + 9.2%

Role of Irinotecan ?

Ychou M, et al. Ann Oncol 2009, 20:1964-70

FOLFIRI x12cy

postop

LV5FU2 x12cy

postop

RANDOMIZATION

DFS

OS

RATIONALE

Two questions

May sequential administration of FOLFOX followed by FOLFIRI improve results ?

Why should the chronology be imposed ?

RATIONALE

MIROX strategy for resectable metastases

6FOLFOX7 (oxa. 130mg/m²) followed by 6FOLFIRI To reduce occurrence of oxaliplatin-related neuropathy, To increase efficacy (absence of cross resistance)

Perioperative OR postoperative chemotherapy Personalized strategy To limit selection bias

Prior phase II study in patients with resectable MCRC N=47 (periop, N=22 ; postop, N=25) No grade 3 neurotoxicity Survivals : 2-yr DFS 47%, and 2-yr OS 89%

Taïeb J, et al. J Clin Oncol 2005, 23:502-9

RATIONALE

DESIGN OF THE PHASE III STUDY

FOLFOX7 – FOLFIRI (N=142)

FOLFOX4 (N=142)

RANDOMIZATION

4-6 preop cycles recommended

Surgery Surgery

N=284From May 2004 to June 2010

N=284From May 2004 to June 2010

INCLUSION CRITERIA

Histologically documented colorectal adenocarcinoma

Resected or resectable metastases

Only one metastatic site: liver, lung, ovary, or peritoneum

Age : 18-75

PS: 0-2

In case of prior adjuvant FOLFOX after resection of the primary:

interval > 12 months required

Primary endpoint :

Disease-free survival (DFS)

Secondary endpoints :–Overall survival–Objective response rate with perioperative chemotherapy,–Resection rate (R0, R1, R2) with perioperative chemotherapy,–Safety (NCI CTC v2)–Health related Quality of Life (EORTC QLQ C-30)

Sample Size

- Superiority study, power of 80%, 2-sided test = 0.05,

- Δ 2-yr DFS rate : from 30% (FOLFOX4) to 45% (FOLFOX7-FOLFIRI)

• 284 patients to be enrolled

• 188 events required

ENDPOINTS

STRATIFICATION CRITERIA

Periop vs. postop chemotherapy

Surgery alone vs. radiofrequency ablation +/- surgery

Blumgart’s score (0-1 vs. 2-3 vs. 4-5)

Disease-free interval (months) <12 ≥12

Primary tumor N+ N0

Number of metastase(s) ≥1 1

Largest met. size (cm) >5 ≤5

Preop CEA level >200 ≤200

Fong Y, et al. Ann Surg 1999, 3:309-21

CONSORT DIAGRAM

FOLFOX4 arm

Randomized: N=284

Treatment allocation

Median follow-up : 50.4 months

FOLFOX7 – FOLFIRI arm

N=142N=142

Treated N=140N=142

ITT analysis N=140N=142

PATIENT’S CHARACTERISTICSFOLFOX4(N=142)

FOLFOX7-FOLFIRI(N=142)

Age <70, % 77 82

Male, % 64 70

ECOG PS 0-1, % 93 93

Liver met. Site, % 83 84

One metatasis, % 51 52

Largest met. Size <5cm, % 86 85

Synchronous met., % 55 59

Primary : node positive, % 58 57

Prior adjuvant chemo, % 23 28

Preop CEA level, mean ratio (V/ULN) 9.9 8.1

TREATMENTSFOLFOX4(N=142)

FOLFOX7-FOLFIRI(N=142)

Treated patient 142 140

Median oxaliplatin dose (mg) 1385 1218

Median oxaliplatin or irinotecan-base cycles 9 12

Peri-operative chemotherapy, n (%) 85 (60) 83 (58)

Response rate after pre-operative chemo, n (%) 42 (49) 41 (50)

Met. Surgery after pre-operative chemo, n % 68 (80) 73 (88)

R0 resection after pre-operative chemo, n % 61 (90) 61 (84)

TOXICITYNCI CTCAE v2, grade 3-4 (%) FOLFOX4

(N=142)FOLFOX7-FOLFIRI

(N=142)

Neutropenia 32 22

Anemia 2 0

Thrombocytopenia 5 9

Febrile neutropenia 2 <1

Nausea 3 9

Vomiting 2 2

Mucositis / Stomatitis 1 2

Diarrhea 10 21*

Cutaneous 0 <1

Alopecia (Gr. 2) 6 6

Neurotoxicity 24 16

Arm 2-yr rate,%

Median[95% CI]

HR[95% CI]

P value

FOLFOX4 48.2 22.4[17.9-36.2]

FOLFOX7-FOLFIRI 49.3 23.0[19.7-35.6]

0.97[0.72-1.31]

0.856

DFS

DISEASE-FREE SURVIVAL

Arm 2-yr rate,%

Median[95% CI]

HR[95% CI]

P value

FOLFOX4 87.5 NR

FOLFOX7-FOLFIRI 90.2 NR 1.07[0.68-1.70]

0.764

OS

NR, not reached

OVERALL SURVIVAL

Arm 2-yr rate,%

Median[95% CI]

Postoperative 60.5 39.9[26.9-NR]

Perioperative 40.3 23.0[15.2-22.4]

DFS

NR, not reached

DFS POSTOP VS PERIOP

Arm 2-yr rate,%

Median[95% CI]

Postoperative 60.5 39.9[26.9-NR]

Perioperative 40.3 23.0[15.2-22.4]

DFS

NR, not reached

DFS POSTOP VS PERIOP

Populations not comparable

39.6% synchronous mets

66.0% synchronous mets

MIROX strategy is not superior to FOLFOX4.

Results in both arms were better than expected, with a 2y-DFS

over 45%, and a 4-yr survival over 70%.

Survival difference between perioperative and postoperative

schedules mainly explained by differences in patient’s profiles.

Planned:

Multivariate analysis focusing on known prognostic factors, and

chronology of chemotherapy.

Overall survival update.

CONCLUSIONS

AcknowlegmentsPATIENTS AND THEIR FAMILIES,

INVESTIGATORSAVIGNON: Laurent MineurBEAUVAIS: Jean-Yves DutelBORDEAUX: Denis SmithBRIEY: Patrick BruckerCALAIS: Zoher MeradDIJON: Michel FleschLA ROCHE/YON: Roger FarouxLIBOURNE: Dominique AubyLILLE: Mohamed Hebbar, Eric Vaillant, Philippe Martin, Stéphanie Truant, François-René Pruvot, Christophe Mariette, Jean-Pierre TribouletMONTPELLIER: Marc Ychou, Eric AssenatPARIS: Aimery de Gramont, Thierry André, Christophe Louvet, Christophe Tournigand, Frédérique Maindrault-Goëbel, Mostepha Bennamoun, Ahmed Khalil, Julien TaïebPESSAC: Jean-Louis LegouxSENLIS: Elisabeth CarolaSURESNES: May Mabro

BIOSTATISTICIANS : CGFL (Dijon)Cécile Dalban, Franck Bonnetain

GERCOR (Paris)Benoist Chibaudel, David Brusquant, Alexandra Hadengue, Dominique Notelet …

SANOFI-AVENTIS Youssef Yataghene